Abstract
Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognition of the AU-rich elements (AREs) within the 3′-UTRs of mRNAs, participates in the pathogenesis of liver diseases. However, whether TTP regulates mRNA stability through other mechanisms remains poorly understood. Here, we report that TTP was upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of CCL2 and CCL5 through promotion of N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP could markedly ameliorate hepatic injury in vivo. TTP regulated the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promoted TTP-mediated RNA destabilization. Moreover, induction of TTP upregulated expression levels of WT1 associated protein, methyltransferase like 14, and YT521-B homology N6-methyladenosine RNA binding protein 2, which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of liver injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a potentially novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.
Highlights
Acute liver failure (ALF) is a critical disorder with a frequently fatal outcome and a 30% mortality [1]
We initially examined whether TTP is important in the pathogenesis of ALF
H&E staining showed that the area of hepatic necrosis in the control was diminished in the TTP vector–treated group injected with CCl4 or APAP (Figure 1E and Supplemental Figure 1I)
Summary
Acute liver failure (ALF) is a critical disorder with a frequently fatal outcome and a 30% mortality [1]. ALF has emerged as a public health issue around the world that occurs generally in patients who do not have preexisting liver disease. ALF can be caused by a series of risk factors, including paracetamol toxicity, hepatic ischemia, viral and autoimmune hepatitis, drug-induced liver injury from prescription drugs, and herbal and dietary supplements [2]. Various cells, such as hepatocytes, macrophages, and endothelial cells, secrete cytokines and chemokines (CC motif chemokine ligand 2 [CCL2], CC motif chemokine ligand 5 [CCL5], CXC motif chemokine ligand 10 [CXCL10], and so on) to recruit hepatic immune cells, especially macrophages, to the injury sites [4, 5]. Hepatocytic CCL2 has been reported to promote macrophage infiltration in APAP-induced liver injury [8]
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